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Polycystic Kidney Disease Gopi Rangan, Staff Specialist, Renal Medicine Westmead Hospital

Polycystic Kidney Disease - Pkdiet Nov 2010 (Polycystic Kidney...Autosomal Recessive Polycystic Kidney Disease ... (iii) Altered stoichometry of the polycystins: Evan et al. Kidney

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Polycystic Kidney Disease

Gopi Rangan, 

Staff Specialist, Renal Medicine

Westmead Hospital

Autosomal Dominant Polycystic Kidney Disease

• Incidence: 1:1000 live births

• Characteristic feature: multiple fluid‐filled cysts in the kidney, liver, pancreas and other organs 

• Renal manifestations‐ 50% develop kidney failure by age 60‐ hypertension‐ renal pain‐ haematuria‐ urinary tract infection‐ nephrolithiasis

• Other associations‐ CVS (valve abnormalities, LVH)‐ GIT (liver/bilary cysts, diverticulum, hernia)

‐ Intracranial and other aneurysms‐ Vascular aneurysm‐Male infertility

PKD1 gene  

• PKD1 gene (16p13.3 ; 53 kB, 46 exons, 15 kB mRNA, encodes polycystin‐1 protein)

• Mutations account for 85% of all ADPKD 

• 270+ different types of mutations described (produce truncated protein; often unique to a single  family; missense mutations much less common)

• Gene complexity makes mutation screening labour‐intensive 

• Mutation of the 5’ portion of the gene may have a more severe phenotype

Polycystin‐1• Large transmembrane protein (m.w. 500 kD)

• Large extracellular N‐terminal region contains several specific motifs

• 11 transmembrane domains

• Multifunctional protein with important functions in cell/matrix adhesion and ciliary function

• C‐terminal tail enters nucleus and regulates cell signaling after cleavage, possibly initiated by polycystin‐2 and initiated by mechanical stimuli

Polycystin‐2 (= TRPP2)• Transmembrane protein (m.w. 150 kD)

• Cytoplasmic N‐ and C‐terminal domains with 6 transmembrane domains

• New member of the transient receptor potential (TRP) family of ion channels, as it is ion channel with some selectivity for calcium ions

• Functions in multiple locations, including plasma membrane, endoplasmic reticulum and the primary cilia

• PC‐1 and PC‐2 function together as well as independently in a variety of subcellular compartments

PKD2 gene • PKD2 gene (4q21 ; 15 exons, 5 kB, mRNA, encodes polycystin‐2 protein)

• Mutations account for 15% of all ADPKD 

• 70+ different types of mutations (truncated protein, unique to a single  family; missense mutations much less common)

• No obvious genotype/phenotype correlations identified

• Disease phenotype of both PKD1 and PKD2 mutations are similar, except that PKD2 mutation is characterised by later onset of end‐stage kidney failure

Wilson PD. N Engl J Med 2004;350:151-64.

Autosomal Recessive Polycystic Kidney Disease

• Incidence: 1:20 000 live births

• Characteristic feature: childhood disease consisting of cystic kidney with congenital hepatic fibrosis

• Manifestations‐majority present in utero or in newborn with kidney enlargement and biliary dysgenesis‐ less commonly present with late‐onset portal hypertension or cholangitis

• Less common AR‐inherited cystic kidney diseases‐ Nephronophthisis (NPHP)‐ Bardet‐Biedl syndrome (BBS)‐ Joubert syndrome (JBTS)‐Meckel‐Gruber syndrome (MKS)

Wilson PD. N Engl J Med 2004;350:151-64; Gattone VH. Curr Opin Pharmacol 2005, 5:1–8

PKHD1 gene  • PKHD1 gene  (6p21, 500kb, 67 exons, 16kB mRNA, encodes fibrocystin/polyductin)

• 100% of all ARPKD

• 300+ disease‐causing mutations

• Majority of mutations unique to a single family

• Two truncating mutations may be associated with a more severe phenotype

Fibrocystin• Large receptor‐like membrane‐associated protein (m.w. 450 kD)

• Single transmembrane domain, large extracellular N‐terminal region and small cytoplasmaic C‐terminal tail

• Has functional similarity to hepatocyte growth factor receptor, and therefore may function as a receptor or a ligand

• Expressed in cortical and medullary collecting ducts of the kidney as well as biliary and pancreatic ducts (consistent with disease distribution of ARPKD). 

• Located in multiple subcellular locations (basolateral membrane, cytoplasm, cilia)

• Cleavage of the ecotodomain and generation of cytoplasmic fragment translocate to the nucleus, possibly in response to stimulation of intracellular calcium or protein kinase C activation. May form a complex with PC‐2, but its exact function is unknown.

Menezes et al. Kidney Int, 66 2004, 1345–1355

However, there is significant inter‐ and intra‐family phenotypic heterogeneity in ADPKD.  This, together with the fact that cyst formation is focal (only 1‐5% of nephrons develop cysts) and slowly progressive through life, suggest that PKD gene mutation predisposes the kidney to cyst formation, but that other factors, possibly environmental or epigenetic mechanisms, must contribute to cyst formation.

Some theories to explain these observations include:

1.  Two‐hit hypothesis (loss of heterozygosity, LOH)i.e. germ‐line mutation in one allele

+ acquired postnatal somatic mutation in the second allele (?toxins, ?aging ? Ischaemia, episodes of tubular injury)

2. Haploinsufficiency, modifier genes, epigenetic mechanisms 

3. Altered stoichometry of the polycystins

The phenotypic heterogeneity and natural history of ADPKD is also highly relevant to the design of clinical trials and future therapeutics:

1. Identifying who will progress (e.g. renal volume >1500 mls, new biomarkers)

2. Need to treat asymptomatic patients for decades and therefore intervention needs to be well tolerated (e.g. low general toxicity and/or targeted to the site cyst formation) 

Polycystin-1 is needed for normaltubulogenesis in kidney development

Polycystins are also probably required forNormal tubular regeneration later in life

In ADPKD, is cyst formation partly due to episodes of acute tubular injury later in life?

In ADPKD, is cyst formation partly due to episodes of acute tubular injury later in life?

Chemically-induced model of PKD

• Sprague-Dawley rats

• 1.06% diet containing 2-amino-4,5-diphenylthiazole (DPT) for 4, 8, 12, and 30 weeks

•DPT induced two types oftubular change: - progressive cystic change of all CDs; -foci of tubular hyperplasia in the cortex, which with time became atrophic.

•These changes have a number offeatures in common with human ARPKD and medullary cystic PKD (nephronophthisis)

Carone et al. Kidney Int 33 1988, 8-13; Darmedy et al. Lancet, 547-550, 1970

Birth and Growth of Cysts in ADPKD

Nature of cyst formation• Hundreds, ranging in size from a pinhead 

to the size of a grapefruit

• Cysts arise in renal tubules when epithelial cells undergo focal proliferation

• Initially this leads to “diverticula” from the nephron, which progressively increase in size 

Postulated mechanisms of cyst formation • An early and sustained proliferation of 

tubular epithelial cells due to loss of function of growth repressor genes (polycystins, fibrocystin)

• Abnormal solute‐driven luminal chloride and fluid secretion, which is largely cAMP and vasopressin –dependent, and a manifestation of epithelial dedifferentiation due to loss of polycystins/fibrocystin

Phenotypic characteristics of normal tubular and cystic epithelial cells 

Normal tubular epithelial cell Cystic tubular epithelial cell

Normal growth‐ Low rate of cell division ‐ Low rate of apoptosis‐ Planar polarity

Differentiated‐ polarized‐ reabsorptive‐ normal concentrating capacity‐ form branching tubules in collagen gels‐ normal cell‐cell/matrix interactions

Abnormal growth‐ high rate of cell division‐ high rate of apoptosis‐ loss of planar polarity

De‐Differentiated‐ polarity defects (e.g. EGF receptor)‐ secretory‐ reduced concentrating capacity‐ form cysts in collagen gels‐ abnormal cell‐cell/matrix interactions (e.g. reduced E‐cadherin)

N.B. Phenotype of the cystic epithelial cell is not ‘malignant’ but it is also not unambiguous. It probably evolves with time and local environmental conditions

Torres et al. 2007

Focal nature of cyst formation in ADPKD and slow adult onset

• Every cell of the nephron and collecting harbors the PKD1 or PKD2 germline mutation, but only 1‐2% of the nephrons or collecting ducts develop cysts. 

• Potential explanations of this observation are:

(i) that ADPKD is due to a “two‐hit” mechanism, in which an inherited germline mutation is compounded by a second somatic mutation.

(ii) Haploinsufficiency

(iii) Altered stoichometry of the polycystins

Evan et al. Kidney Int 16: 743-750, 1979

Epithelial hyperplasia Micropolypformation

Ultrastructural and histological evidence of cystic epithelial proliferation in human ADPKD

Grantham et al. Kidney Int 31: 1145-52, 1986

Modified from Nadasdy et al. J Am Soc Nephrol 1995; 5:1462-1468

Mean proliferative (PCNA) index is increased in human cystic renal diseases

0.28

2.58

10.5

3.61

11.18

0

2

4

6

8

10

12

Normal Kidney

ADPKD ARPKD Acquired cystic renal disease

Renal cell carcinoma

Which segment of the nephron do cystic epithelial cells arise from?

Grantham et al. Kidney Int 31: 1145-52, 1986

ADPKDCysts are derived from all nephron segments but both human and PKD1-null mice studies show that they arise predominantly from the distal nephron (LOH, DCT, CD)

- Heggo 0. J Path Bacterlol 1966:91:31 1-3 15.- Baert L: Kidney Int 1978:13:519-525.-Faraggiana T et al. Lab Invest 1985:53:575-579- Verani I,Silva P0. Mod Pathol 1988:1:457-463

ARPKDCystic dilatation arises almost exclusively in the collecting duct

- Verani R, Walker P, Silva P0: Pediatr Nephrol 1989:3:37-42- Heggo 0, Natvig JB. Acta Pathol Microbiol Scand 1965:63:500-512.- Osathanondh V, Potter EL. Arch Pathol 1964:77:466-473.- Holth et al. Lab Invest 1990:62:363-369.

Acquired cystic renal diseasePredominantly proximal tubules

- Deck MA, et al. Surg Pathol 1988:1:391-406.- Ishlkawa I: In: Gardner IW Jr. Bernstein J, Eds. The Cystic Kidney. Boston: Kluwer: 1990:351-377.-Feiner HD, Katz LA, Gallo OR: Urology 1981:17:260-264.

Morphometric evidence to suggest cyst expansion is due to an increase in cell number and not simply due to ‘stretching ‘ and ‘thinning’ of individual cells in human ADPKD

• Normal proximal tubule diameter = 62.4 x 10-4 cm

• To grow a 1 mm cyst derived from the proximal tubule to 8 cm, surface area would need to increase from 19.6 x 10-4

cm2 to 201 cm 2, which represents a 100, 000-fold increase.

• However, the surface area of individual cells only increases, at the most 15-fold, from 170 x 10-8 to 2530 x 10-8

cm2

• Therefore, cell number must increase at least 10,000-fold to produce an 8 cm cyst

Grantham et al. Kidney Int 31: 1145-52, 1986

Du and Wilson. Am J Physiol 269, C487-95, 1995

Proliferation is also abnormal in experimental models of polycystic kidney diseases:Loss of planar cell polarity

Germino 2005 Patel et al. 2008

Natural history of ADPKD and risk factors for progression

In ADPKD, there is a long asymptomatic period when GFR can be well preserved but there is significant kidney enlargement

Risk factors for progression

1. Age at diagnosis (symptomatic) (<30 y.o, renal survival 10 years)

2. Genotype (PKD1 faster than PKD2; Why?)

3. Kidney size (CRISP study; >1500 ml = GFR decreased by -4 ml/min/year)

4. Family history of end-stage renal failure

5. Others: combination of hypertension, diagnosis and gross haematuria before 30, had zero renal survival at age 48

Why does kidney failure occur with cyst expansion?

Not entirely clear, because the cyst burden can be significant, yet GFR is well preserved.

Glomerular haemodynamic factors (that is, increased glomerular hyperfiltration in other types of CKD) do not seem to be have a major role, as: (i) secondary glomerular injury (FSGS) is not

increased in ADPKD(ii) Uninephrectomy in humans, does not seem

to have a detrimental effect on progression to end-stage renal failure (Zeier et al. 1992), whereas in experimental animals it does (Kang et al. 2000, Keier)

Progression to end-stage renal failure correlates best with the development of interstitial fibrosis and vascular sclerosis

Therefore, the presence of cysts could lead to interstitial fibrosis by:

1. Compression of surrounding tissue with slow enlargement of cysts, leading to loss of peritubular capillary blood supply and tubular obstruction

2. Increased production of profibrotic growth factors and chemokines by cystic epithelial cells

Renal histology in early and advanced human ADPKD

Zeier et al. Kidney Int 42, 1259-65,

Glomerular pathology

Interstitial fibrosis

Vascular sclerosis

Onset of interstitial fibrosis coincides with the decline in renal function

Phillips et al. 2007

Timecourse of peritubularcapillary distribution in the outer medulla of control and LPK rats.Control Lewis rat demonstrates an extensive peritubular capillary network that is more dense than the cortical network. By week 3 LPK rats have very few normal tubules in the outer medulla and the peritubular capillary network is almost non-existent. Some individual capillaries remain. LPK rats at week 6, 12 and 24 demonstrate almost no peritubularcapillaries. Some vessels remain and these may be remnant capillaries, vasa recta or new vessels, and these are fewer in weeks 12 and 24 compared to week

Peritubular capillaries of the outer medulla disappear early in LPK rats

O’Brien et al. (unpublished)

Small animal models of PKD

• No currently available genetically- and non-genetically orthologous animal model completely recapitulates human ADPKD or ARPKD

• Homozygous deletion of PKD1 gene is embryonic lethal, whereas heterozygous deletion has focal cyst formation and very slow to progress with little, if any, deterioation in renal function

• The best models for testing new therapies are those with diffuse cyst formation and relatively slow progression

- e.g. - bpk mouse and jck mouse- Pck rat- Han:sprd rat

• Often necessary to prove drug efficacy in more than one model because of these limitations (e.g. one that is genetically and non-genetically orthologous) – jck mouse + pkdws25

mouse

Guay-Woodford L. Am J Physiol Physiol (2003) 285: F1034–F1049.

Cellular Mechanisms of Cystogenesis and Progression of Cyst Growth

1. Tubular epithelial cell proliferation

2. Tubular epithelial cell dedifferentiation

‐ EGF receptor mislocalization

‐ fluid secretion

‐ reduced cell‐cell adhesion

‐ increased cell matrix adhesion

‐ planar cell polarity

Factors initiating and accelerating tubular epithelial cell proliferation

Genetic Factors

Cilia‐localised proteins (polycystin‐1, polycystin‐2)

Modifier genes

?Post DNA methylation

Circulating Factors

ADH (water intake)

Local Paracrine Factors and Cyst Fluid Constituents

Growth factors (EGF, VEGF, KGF)

Extracellular matrix (laminin, SPARC)

Angiogenesis

Environmental Factors

Episodes of renal tubular injury

Caffeine

Loss of function in cilia‐localised proteins

Cyst formation

Homozygosity and modifier genes?Episodes of acute tubular injury

Other environmental factors

Cyst enlargement

Interstitial Fibrosis

Glomerular hypertension and 

glomerulosclerosis of remaining  nephrons

Loss of functioning renal tissue

KIDNEY FAILURE

Increased matrix depositionRelative tubulointerstitial ischaemia Epithelial-mesenchymal transition

Atubular glomeruliFormation of isolated cysts

Tubular epithelial cell proliferation +

Tubular epithelial cell dedifferentiationCell cycle inhibition

Tubular epithelial cell proliferation +

Tubular epithelial cell dedifferentiation

Current approaches to treating polycystic kidney disease

1.  Treat hypertension (Target BP 130/80; ACEI/ARB)

2. Maintain appropriate body weight

3. Diet (limit sodium, avoid high‐protein diet; limit caffeine intake; adequate water intake)

4. Monitoring disease progression (dependent on renal function)

5. Screening other family members with ultrasound

Future approaches to treat cystic tubule cell proliferation and fluid section

1.  Suppressing intracellular cAMP levels (vasopressin receptor antagnoist, somatostatin agonists)

2. Reducing basolateral and luminal chloride transport (NKCCl and CFTR inhibitors)

3. Reducing intracellular calcium (triptolide, calcium channel blockers)

4. Inhibition of cell cycle pathways

‐ EGF receptor antagonists

‐ Reducing activation of mTOR protein kinase (sirolimus)

‐ Reducing cyclin‐dependent kinase activation (roscovitine)

‐ MEK inhibitors

‐ Src inhibitors

5. Better methods to predict who will progress to end‐stage renal failure

‐ biomarkers of progression (urinary MCP‐1 levels)

‐ improvements in genetic testing, epigenetic factors

Vasopressin receptor antagonists

Greenberg and Verbalis 12:2124-30, Kidney Int,

Intracellular signal transduction abnormalities

Reduced intracellular calcium

Increased intracellular cAMP

Signal transduction activation (ERK, MEK, B‐Raf, mTOR)

Apoptotic regulatory proteins (caspase)

Cell cycle regulatory proteins

Protooncogenes

MicroRNAs

CRISP KI 64: 1035, 2003

15 seconds 30 seconds 60 seco

Bello-Reuss Kidney Int 60: 37, 2001

Bello-Reuss Kidney Int 60: 37, 2001

Dicks et al, Clin J Am Soc Nephrol 1: 710, 2006

Genotype, family and proteinuria are risk factors for renal events

Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) 

• N=232 patients with early ADPKD without aztoaemia

• Renal enlargement occurs in a quantifiable, exponential manner and can be correlated directly with the decline in renal function (about 5% per year)

• The increase in kidney volume was about equal between right and left kidneys and was twice as fast in patients with the PKD1 mutation compared to PKD2 mutation

• A baseline total kidney volume >1500 ml was associated with a declining GFR

• In comparison with GFR, which declines very slowly in early stages of ADPKD and therefore is not a robust marker of disease progression, MRI assessment of renal volume seems to provide a promising tool for monitoring early disease progression and assessing the efficacy of therapeutic interventions

Grantham et al. N Engl J Med 354: 2122, 2006

Harris et al. J Am Soc Nephrol 17: 3013, 2006

Trends in the incidence of ESRD due to PKD

Trends in prevalence of ESRD due to PKD

End‐stage renal failure due to ADPKD in Australia and New Zealand

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5Follow-up Time (Years)

1995-2004Survival on dialysis by PKD status

5-year survival is better in PKD patients. The survival advantage was most marked in the first 2 years (RR 0.31 for first 2 years vs 0.52 for the subsequent years).

PKD

Non-PKD

Rangan GK, Shtangey, McDonald SP (in preparation)

5th most common cause of ESRF

ANZDATA report 2007

Methods• Sample consisted of all ANZ patients over the age of 20

and whose first treatment was dialysis. The characteristicsof patients with or without ESRF due to PKD wereanalysed from the ANZ Dialysis and TransplantationRegistry for the last 10 years (1995‐2004);

• Diabetics were excluded from both PKD and non‐PKDpatients.

• Data for haemoglobin and EPO were analysed from 2000‐2004

• Univariate and multivariate analyses were performed.

Age

Figure 1. Patients with PKD are younger than non-PKD dialysis patients (55 vs 61 years of age).

50

55

60

65

70

PKD Non-PKD

N=1318 N=12 828

P<0.0001

Gender

Figure 2. Men were less likely to have PKD as as a cause for ESRF (Odds ratio, OR: 0.85, P=0.0046).

6

7

8

9

10

11

Female Male

10.1%

P=0.0046

85

87

89

91

93

95

Female Male

91.3%

% o

f mal

es a

nd fe

mal

es w

ith P

KD

% o

f mal

es a

nd fe

mal

es w

ithou

t PK

D

8.7%89.9%

Vascular disease

Figure 5. Vascular disease was reduced in PKD patients

0

8

16

24

32

40

PKD

No PKD

Coronary artery

disease

% o

f tot

al P

KD

or n

on-P

KD

pop

ulat

ion

Peripheral vascular disease

Cerebrovascular disease

Smoking          Hypertension     Lung Disease

Figure 6. PKD patients smoked less and had reduced chronic lung disease, but hypertension was increased slightly.

0

3

6

9

12

15

% o

f tot

al P

KD

or n

on-P

KD

pop

ulat

ion

70

80

90

100

0

4

8

12

16

20

24

28

PKD No PKD PKD No PKD PKD No PKD

Mean Hb is higher in PKD

Figure 7. Patients with PKD have a higher Hb

100

105

110

115

120

125

130

PKD Non-PKD

123+18 117+17

Use of EPO is lower in PKD• Among non‐PKD patients, 11.89 % did not use and 88.11%

used EPO agents

• Among PKD patients, 13.83% did not use and 73.16% usedEPO agents. The difference was significant at p=0.001.

• PKD patients are less likely to use EPO agents than non‐PKDpatients, OR=0.37, 95% CI: [0.31; 0.44]. After adjusting forage, gender and race, PKD disease is still a significantpredictor of EPO use.

Survival of PKD patients

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5Follow-up Time (Years)

Australian dialysis patients: 1995-2004Kaplain-Meier estimates for survival on dialysis by PKD status

Figure 8. 5-year survival is better in PKD patients. The survival advantage was most marked in the first 2 years (RR 0.31 for first 2 years vs 0.52 for the subsequent years).

PKD

Non-PKD

Clinical Trials

Overall aim: The efficacy of interruption of the renin-angiotensin-aldosterone system (RAAS) on the progression of cystic disease and onthe decline in renal function in autosomal dominant kidney disease(ADPKD) will be assessed.

Study Design: Two concurrent multi-centre randomized, double-blind,placebo control clinical trials targeting different levels of kidney function:

STUDY A: early disease defined by GFR >60 mL/min/1.73 m2with primary outcome as change in total kidney volume, as assessed byabdominal MR at baseline, 2 years and 4 years followup; and

STUDY B: moderately advanced disease defined by GFR 30-60 mL/min/1.73 m2 with primary outcome as time to the 50% reduction ofbaseline eGFR, ESRD (initiation of dialysis or preemptive transplant) ordeath, followed for 4-6 years with average length of followup being 5years.

Participants will be recruited and enrolled, either to Study A or B, over thefirst two years.

Total enrollment: 1018 patients in U.S. centres only

Study timetable: Start January 2006 and expected completion:December 2011

Sponsors: NIH, Ingelheim Pharmaceuticals, Merck, PKD Foundation

www.clinicaltrials.gov accessed May 9th 2007

Sirolimus

• Clinical trials in humans to test the efficacy of various agents in PKD are currently underway. One such agent is sirolimus

• Sirolimus is an immunosuppressant drug with anti‐proliferative effects. It is known to inhibit mTOR, an enzyme involved in mRNA translation that is upregulated in PKD

• Sirolimus given to ADPKD rats inhibits cystogenesis via its anti‐proliferative effects. 

• Evidence suggest it may have other mechanisms of action that relate to angiogenesis

Shillingford et al. PCNAS (2006) 103, 5466-71

Presenter
Presentation Notes
This diagram summarizes the various molecular mechanism that are thought to occur in cystic tubular epithelial cells. [Here] is the primary cilia and the location of the proteins implicated in PKD. Loss of function for these proteins is a central trigger. In particular I’d like to draw your attention to the mTOR pathway, it is colored blue indicating it is up-regulated in PKD. mTOR is a serine-threonine kinase that controls protein synthesis via direct and indirect phosphorylation of downstream targets required for mRNA translation. In green are potential therapeutic agents for the treatment of PKD and sirolimus is an important mTOR inhibitor. Clinical trials for the treatment of ADPKD with sirolimus have commenced. These are based on evidence provided by animal models. For example in Han:SPRD rat models of ADPKD sirolimus significantly reduced cystogenesis, kidney enlargment and renal function loss. However the effects of sirolimus on PKD may be due to more than simply reducing epithelial cell proliferation Sirolimus has also been shown to inhibit angiogenesis in mouse models of metastatic cancer It is also associated with impaired VEGF production and VEGF-induced endothelial cell proliferation. The effect of sirolimus in AR model of PKD has yet to be investigated. Its effect on angiogenesis and VEGF expression in PKD is also unknown.

T‐PO‐1229: Sirolimus for ADPKD: study design and baseline data of the first patientsA. Kistler, D. Poster, M. Struker, D. Weishaupt, F. Tschirch, RP Wuthrich, AL Serra.

Clinic for Nephrology, Institute of Diagnostic Radiology, University Hospital, Zurich, Switzerland

Proceedings of the World Congress of Nephrology, April 21‐25th 2007, Rio de Janeiro, Brazil (page 402)

• Design: Prospective RCT open‐label trial involving. Kidney volume by MRI at study month 0 and 6. Patients with documented progression are randomized 1:1 ratio to a standard treatment or sirolimus 2 mg/day for 18 months. Recruitment started May 2006 and will last December 2007

• Inclusion criteria: 100 ADPKD‐patients aged 18‐40 years with CrCl >70ml/min before screening 

• Outcome measures: Primary endpoint is percentage change of total kidney volume determined by MRI at study month 12 and 24. Secondary endpoints are CrCl, proteinuria, hypertension and safety.

• Results: By November 2006, 108 patients screened, 60 were included in the study and 9 patients have completed the 6 months baseline period. The 60 patients have a mean age of 30 (18‐40), 62% were male, 43% have hypertension, mean CrCl was 108 ml/min (range 69‐153). 8 of the 9 patients completing the baseline period showed volume progression and were randomized to the treatment or the control group. The mean total kidney volume was 1150 ml. 

• Conclusion: Recruitment rapid; MRI volumetry can be detected reliably.

Potential pitfalls in designing experimental studies in PKD: Sirolimus as a case example

2002+: Animal models consistently showedsirolimus consistently reduced cyst size

June 2010: Results of first clinical trianot so positive

Rangan, Burgess, Schwensen, Harris et al. 2009

Designing experiments: Timing is everything - Sirolimus as a case example

Sirolimus RxVehicle RxSirolimus RxVehicle Rx

Starting treatment before maximal kidney growth

(week 3 to 10)

Starting treatment when maximal kidney growth was present

(week 10 to 20)

Schwensen et al. 201

Vasopressin V2 receptor antagonists (tolvaptan)

Reduce cAMP levels

Phase III clinical trials underway 

Including 7 centres in Australia

Octreotide

• Somatastatin acting on SST2 receptors inhibits cAMP

• Octreotide (somatostatin analogue)

• Clinical trial in Italy

Chapman et al (FDA ) et al. 2007

Challenges for therapy

• Identification of who will progress

• Treatment may be for decades (side‐effects, compliance etc)

• Need to act on multiple signaling pathways

• Stage‐specific therapies (e.g. anti‐proliferative early, V2 antagonists later)

Westmead Hospital

David Harris

Kam Ghatora 

Jane Burgess

Kristina Schwensen

Rabia Chaudhry

Kristal O’Brien

Daria Stepanova

Richard Allen, Paul Robertson, David Harris

Macquarie UniversityJacqueline Phillips (Murdoch University)

Animal Resources CentreDeborah Hopwood (Animal Resources Centre)

Royal Prince Alfred Hospital

Richard Allen, Paul McKenzie

Adelaide (ANZ Dialysis and Transplant Registry)

Stephen McDonald

Rochester, USA

Peter Harris, Stefan Somlo, Vincente Torres

Singapore

Phillip Kaldis